1-147759016-T-C

Variant names:

• chr1-147759016-T-C
• NM_181703.4:c.223A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_181703.4(GJA5):​c.223A>G​(p.Ile75Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I75F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJA5 NM_181703.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94

Genes affected

GJA5 (HGNC:4279): (gap junction protein alpha 5) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

LOC102723321 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-147759016-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA5	NM_181703.4	c.223A>G	p.Ile75Val	missense_variant	Exon 2 of 2	ENST00000579774.3	NP_859054.1
GJA5	NM_005266.7	c.223A>G	p.Ile75Val	missense_variant	Exon 2 of 2		NP_005257.2
LOC102723321	XR_922079.4	n.82-18545T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA5	ENST00000579774.3	c.223A>G	p.Ile75Val	missense_variant	Exon 2 of 2	1	NM_181703.4	ENSP00000463851.1
GJA5	ENST00000621517.1	c.223A>G	p.Ile75Val	missense_variant	Exon 2 of 2	2		ENSP00000484552.1
GJA5	ENST00000430508.1	c.223A>G	p.Ile75Val	missense_variant	Exon 2 of 2	2		ENSP00000407645.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;D;T
Eigen	Benign	0.030
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.46	N;N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.74	.;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.72	.;.;T
Sift4G	Benign	0.25	T;T;.
Polyphen		0.25	B;B;.
Vest4		0.088
MutPred		0.47		Loss of catalytic residue at L80 (P = 0.237);Loss of catalytic residue at L80 (P = 0.237);Loss of catalytic residue at L80 (P = 0.237);
MVP		0.94
ClinPred		0.73	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-147231124;